Reprotoxins that should be subject to limit values for ...€¦ · area of reprotoxic substances in the scope of their national legislation con-cerning carcinogenic and mutagenic

EuropeanTrade Union Institute

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Reprotoxins that should be subject to limit values for workers’ exposure—Henning Wriedt.....................................................................................................................................Report 137

D/2016/10.574/15ISBN: 978-2-87452-408-0

Reprotoxins that should be subject to limit values for workers’ exposure

Henning Wriedt

Report 137

european trade union institute

Henning Wriedt is a researcher at the Beratungsstelle Arbeit & Gesundheit (Occupational Health & Safety Advice Centre), Hamburg, Germany. Contact: [email protected]

Brussels, 2016© Publisher: ETUI aisbl, BrusselsAll rights reservedPrint: ETUI Printshop, Brussels

D/2016/10.574/15ISBN: 978-2-87452-408-0 (print version)ISBN: 978-2-87452-409-7 (electronic version)

The ETUI is fi nancially supported by the European Union. The European Union is not responsible for any use made of the information contained in this publication.

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Contents

Executive summary ......................................................................................................................4

1. Introduction .......................................................................................................................51.1 Background to the project ......................................................................................................... 51.2 Objectives and limitations ......................................................................................................... 61.2.1 Definition of ‘reprotoxin’ ............................................................................................................ 61.2.2 ‘Relevance’ of a reprotoxin ........................................................................................................ 61.2.3 Appropriateness of an OEL as a regulatory instrument .................................................. 71.3 Method – general definitions ................................................................................................... 71.3.1 Reprotoxins ..................................................................................................................................... 71.3.2 Relevance ......................................................................................................................................... 91.3.3 Relevant reprotoxins .................................................................................................................... 91.4 Method – specific selection criteria .....................................................................................101.4.1 Selection of actual regulatory reprotoxins ........................................................................111.4.2 Assessment of relevance of selected regulatory reprotoxins .....................................121.4.3 Refinement of level of relevance of reprotoxins placed on the market ..................14

2. Results ...............................................................................................................................162.1 Substances toxic to reproduction selected with different

levels of relevance .......................................................................................................................162.1.1 Substances toxic to reproduction considered to be relevant .....................................162.1.2 Substances toxic to reproduction considered to be potentially relevant ..............162.1.3 Substances toxic to reproduction with unclear relevance ...........................................162.2 Additional information provided in Tables 1–3 of the Annex ....................................172.2.1 Special classes of substances toxic to reproduction ......................................................172.2.2 Notes on classification, registration and regulatory processes .................................17

3. Discussion .........................................................................................................................19

Annex ..............................................................................................................................................21

Table 1 List of substances/groups of substances toxic to reproduction considered to be relevant......................................................................................................21

Table 2 List of additional substances/groups of substances toxic to reproduction considered to be potentially relevant ....................................................24

Table 3 List of additional substances/groups of substances toxic to reproduction considered to be of unclear relevance ..................................................25

Explanation of notes in Tables 1–3 .....................................................................................................28

Executive summary

The objective of this project is to identify substances toxic to reproduction (hereafter: ‘reprotoxins’) that are relevant for workers’ exposure via inhala-tion at a considerable number of workplaces in Europe and thus for which an IOELV under the CAD might be suggested.

As a starting point, the terms ‘reprotoxin’ and ‘relevance’ are defi ned for their use in the context of the project. In addition, the conditions under which an OEL would be appropriate as a regulatory tool are refl ected on. Then the methods applied for selecting reprotoxins and for assessing their relevance are detailed. In addition to the reprotoxins already included in Annex VI of the CLP regulation, further substances are considered to be future (or ‘potential’) reprotoxins if they meet certain conditions and are included in the analysis.

The main information sources utilised are the C&L Inventory, the REACH da-tabase on registered substances and compilations of substances included in various REACH processes, all available on the ECHA website.

The analysis resulted in the selection of 141 reprotoxins or groups of repro-toxins, divided into three categories of diff erent levels of relevance. For 66 of them an IOELV under the CAD might be suggested.

In an Annex all selected reprotoxins, complemented by additional informa-tion for further refi nement, are listed.

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1. Introduction

1.1 Background to the project

In its resolution on the improvement of occupational health and safety in the European Union, adopted by the Executive Committee in December 2014, the European Trade Union Confederation (ETUC) called, among other things, for the inclusion of reprotoxic substances in the scope of the Carcinogens and Mutagens Directive (Dir. 2004/37/EC, hereafter: CMD), ‘due to the severity and irreversibility of the health eff ects for workers (especially pregnant wom-en) from exposure to these substances’. With this request, the ETUC intends to generalise the past decision of several EU Member States to include the area of reprotoxic substances in the scope of their national legislation con-cerning carcinogenic and mutagenic substances.

The proposal was made against the background of the decision of the Com-mission, announced in October 2013, to halt the revision of the CMD during its mandate as part of the so-called REFIT programme. One issue of the revi-sion of the CMD was the extension of its scope to include reprotoxic substanc-es. However, even before halting the revision process as a whole, the Commis-sion had already separated the issue of including reprotoxic substances in the scope of the CMD from other issues, among them the derivation of binding OELs for about 25 carcinogens.

For many reprotoxic substances that do not also exhibit carcinogenic proper-ties, eff ect thresholds have been identifi ed below which no adverse eff ects oc-cur. For them, health-based OELs – so-called indicative occupational exposure limit values (IOELVs) – could thus be derived under the CAD that would be protective for reproductive toxicity. We should observe, though, that certain reprotoxic substances might be identifi ed as endocrine disrupting chemicals (EDs) without an eff ect threshold below which no adverse eff ects occur. Once a reprotoxic substance is identifi ed as an ED, no IOELV should be derived for it. Instead, for such substances other regulatory approaches are warranted.

In contrast to BOELs under the CMD, however, when it comes to their im-plementation in national legislation, Member States have the discretion of introducing higher limit values that might not be protective for reproductive toxicity. Nevertheless, establishing IOELVs under the CAD for reprotoxic sub-stances would be an important initial step in protecting workers from the health eff ects of reprotoxic substances.

1.2 Objectives and limitations

The objective of this project is the identifi cation of substances toxic to repro-duction (reprotoxins) that can be considered relevant in the sense that a con-siderable number of workers in Europe are aff ected by exposure to them via inhalation.

In order to do so, two terms need to be defi ned in the context of this project, ‘reprotoxin’ and ‘relevance’. In addition, the exposure routes of the relevant reprotoxins identifi ed have to be assessed, and reprotoxins that are relevant with regard to dermal exposure only are to be excluded.

1.2.1 Defi nition of ‘reprotoxin’

In the context of this project, all substances or mixtures included in Annex VI of the CLP regulation (Reg. (EC) No 1272/2008) classifi ed as R 1A, H360 or R 1B, H360 are considered to be reprotoxins.

Eff ects on fertility and development are communicated by diff erent hazard statements: reprotoxins adverse to fertility are denoted by the hazard state-ment H360F; reprotoxins adverse to development by the hazard statement H360D; and reprotoxins adverse to both fertility and development by the haz-ard statement H360FD.

1.2.2 ‘Relevance’ of a reprotoxin

From an occupational health and safety perspective, the relevance of a repro-toxin is based on:– the number of workers exposed to it; and – the extent of the exposure (level, duration and frequency).

Given that quantitative data for these factors were available, the number of workers could be determined for whom the exposure levels via inhalation were above any threshold for eff ects adverse to reproductive toxicity. Assess-ments of the relevance of individual reprotoxins could then be based on ei-ther the total number of workers exposed to them, or the number of workers exposed to them above their respective eff ect threshold, or a combination of both.

Because, however, the necessary data for the two former factors – that is, number of workers exposed and extent of exposure – are not available, and information on the existence of an eff ect threshold and its size have been de-termined for only a limited number of reprotoxins as yet, the relevance of a reprotoxin cannot be determined by this method. Instead, other criteria have to be employed.

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1.2.3 Appropriateness of an OEL as a regulatory instrument

OELs are major tools for risk assessment of respiratory exposure. There, they serve two main functions:(i) for the design of control measures, they defi ne the minimum level of pro-

tection; and(ii) for the assessment of the eff ectiveness of control measures applied, they

are the yardsticks for the resulting exposure level and, thus, for the neces-sity of improving those control measures.

For dermal exposure, however, OELs might be of scientifi c and regulatory, but not of practical interest due to the absence of suitable instruments for moni-toring dermal exposure at the workplace.

1.3 Method – general defi nitions

The process of identifi cation and selection of ‘relevant reprotoxins’ as dis-cussed in the previous section is done in two steps. First, both terms are spec-ifi ed: which substances should be considered to be reprotoxins in the context of this project, and what criteria should be employed to designate a reprotoxin as a relevant one? Second, specifi c selection criteria for both categories are defi ned that enable the fi nal selection of ‘relevant reprotoxins’ and their al-location to diff erent levels of relevance.

In this section, the fi rst step is addressed: the general schemes for identify-ing reprotoxins and assessing the relevance of substances, respectively, are described, and the concrete combination of both pieces of information is presented.

1.3.1 Reprotoxins

Given the purpose of this report – to provide a list of reprotoxins for which IOELVs under the CAD should be established – substances selected should meet the defi nition specifi ed in Section 1.2, above. For simplifi cation, these reprotoxins will be denoted as ‘actual regulatory reprotoxins’.

Actual regulatory reprotoxins placed on the market can be identifi ed via the publicly available database containing classifi cation and labelling informa-tion on notifi ed and registered substances (C&L Inventory) on the website of the European Chemicals Agency (ECHA) (http://echa.europa.eu/informa-tion-on-chemicals/cl-inventory-database).

In addition to the ‘actual regulatory reprotoxins’, in the context of this pro-ject additional substances are considered to be ‘potential regulatory repro-toxins’. A substance will be considered to be such a ‘potential regulatory reprotoxin’ if one of the following three conditions is met:

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(i) a process of harmonised classifi cation either as R 1A, H360 or as R 1B, H360 was initiated and resulted in adoption by the Committee for Risk Assessment (RAC) of the ECHA by September 2015, but either subse-quent legal procedures have not been fi nalised or the resulting adapta-tion to technical and scientifi c progress (ATP) has not come into force yet; information on such processes is available in the ‘Opinions of the Com-mittee for Risk Assessment on proposals for harmonised classifi cation and labelling’ section of the ECHA website (http://echa.europa.eu/web/guest/opinions-of-the-committee-for-risk-assessment-on-proposals-for-harmonised-classifi cation-and-labelling);

(ii) a process of harmonised classifi cation either as R 1A, H360 or as R 1B, H360 was initiated but not fi nalised by October 2015; information on such processes is available in the ‘Registry of Intentions’ section of the ECHA website, both in the part ‘Current CLH intentions’, (http://echa.europa.eu/web/guest/registry-current-classifi cation-and-labelling-intentions) and in the part ‘Submitted CLH proposals’ (http://echa.europa.eu/web/guest/registry-of-submitted-harmonised-classification-and-labelling-intentions); or

(iii) a substance without a harmonised classifi cation with regard to reprotox-icity has been notifi ed to the ECHA by one or more manufacturers or im-porters either as R 1A, H360 or as R 1B, H360; information on such noti-fi cations is available in the C&L Inventory on the ECHA website (http://echa.europa.eu/information-on-chemicals/cl-inventory-database).

Whereas conditions (i) and (ii) have been checked systematically for all en-tries in the respective list, no such systematic check has been undertaken for condition (iii). Not only is the number of substances with such notifi cations – with more than 1,700 entries – rather large, but the criteria for the individual notifi cation applied by the respective notifi er (manufacturer or importer) are unknown to the public. Therefore, an outside observer is not in a position to assess whether such a notifi cation is justifi ed or not. Such ambiguities are underlined by the observation that for a number of substances only a single notifi er or a minority of notifi ers indicated a notifi cation either as R 1A, H360 or as R 1B, H360, whereas other notifi ers of the same substance indicated ei-ther no notifi cation for reprotoxicity or a notifi cation for suspected reprotox-icity (R 2, H361) only. As a conclusion, substances with a notifi cation either as R 1A, H360 or as R 1B, H360 are included as ‘potential regulatory reprotox-ins’ only if other supporting evidence has been found, such as the inclusion in the risk management option analysis (RMOA) (cf. the ECHA website: http://echa.europa.eu/addressing-chemicals-of-concern/substances-of-potential-concern/pact), the inclusion in the Community Rolling Action Plan (CoRAP) (cf. the ECHA website: http://echa.europa.eu/information-on-chemicals/evaluation/community-rolling-action-plan/corap-table), or the derivation of an OEL at national level.

The reason for considering ‘potential regulatory reprotoxins’ is the expecta-tion that in the foreseeable future many of them will become ‘actual regula-tory reprotoxins’ by inclusion in Annex VI of the CLP regulation classifi ed as R 1A, H360 or R 1B, H360.


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1.3.2 Relevance

In the absence of comprehensive knowledge of both the extent of exposure to the majority of reprotoxins at workplaces in the EU and the eff ect thresholds for reprotoxicity of many of them, surrogate signifi ers have to be employed to assess the relevance of individual reprotoxins.

For substances placed on the market, an initial approach for approximating exposure information is to use information on production or import volume. Such information is publicly available via a database containing information on substances registered under REACH on the ECHA website (http://echa.europa.eu/information-on-chemicals/registered-substances) for reprotoxins above a production or import volume above one tonne per year. For the pur-pose of this report, the following information is of particular signifi cance: registration status (full registration/registration as intermediate/no registra-tion), and tonnage band (in case of full registration).

Included in that database are substances notifi ed as new substances (NONS) under Dir. 67/548/EEC before REACH came into force. For them, less infor-mation is available than for substances registered under REACH. In particu-lar, no information on production volume is publicly accessible.

For certain substances placed on the market, such registration information is not available, however. Active substances for use either in plant protec-tion products or in biocidal products are regarded as being registered under REACH (cf. Art. 15 of the REACH regulation) and are therefore not necessar-ily contained in the above-mentioned database. In the further analysis they are considered to be relevant if they are listed either in the Annex to Commis-sion Implementing Regulation (EU) No. 540/2011 implementing Regulation (EC) No. 1107/2009 concerning the placing of plant protection products on the market, or are contained in the database on biocidal active substances on the ECHA website (http://echa.europa.eu/web/guest/information-on-chemi-cals/biocidal-active-substances).

Exempted from registration under REACH are substances used in medicinal products for human or veterinary use (cf. Art. 2 para 5 of the REACH regula-tion). Thus, also for them no registration information is available. Accord-ingly, in the further analysis such substances are considered to be relevant, given that their use in medicinal products could be identifi ed.

1.3.3 Relevant reprotoxins

The number of actual regulatory reprotoxins as listed in the C&L Inventory on the ECHA website with a harmonised classifi cation as R 1A, H360 or as R 1B, H360, as updated on 30 October 2015, was about 220. That number is reduced in two ways, described in more detail in Section 1.4, below:

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(i) substances also classifi ed as either carcinogens (C 1A, H350 or C 1B, H350) or mutagens (M 1B, H340) are omitted;

(ii) reprotoxic lead and boron compounds are combined to form single entries.

As a result, the remaining number of actual regulatory reprotoxins is reduced to less than 100. For potential regulatory reprotoxins, due to their much smaller number, no such reduction was deemed necessary.

The relevance of each substance in the resulting sample of reduced actual regulatory reprotoxins and all potential regulatory reprotoxins is assessed by a tiered approach consisting of the following four steps:

As a fi rst step, for each substance presumably placed on the market it was examined whether it has been registered under REACH and, if so, either with a full registration, or with a registration for use as an intermediate only, or as a NONS substance.

As a second step, for reprotoxins presumably placed on the market but with-out a registration under REACH, it was checked whether they are listed either as an active substance approved for use in plant protection products or as a biocidal active substance.

As a third step, for all remaining reprotoxins presumably placed on the mar-ket – those without a registration under REACH, without a listing either as an active substance for plant protection or as a biocidal active substance – it was checked whether they are used in medicinal products.

As a fourth and fi nal step, it was checked whether any of the remaining repro-toxins presumably placed on the market (no registration under REACH, listed neither as an active substance for plant protection nor as a biocidal active substance, not used in medicinal products) are currently, or were in the past, subjected to certain regulatory processes at European level in the context of the REACH regulation, the CLP regulation or the CAD, or at national level in Germany or the Netherlands. Such processes are:(i) in the context of the REACH regulation and the CLP regulation the in-

clusion in the Candidate List of Substances of Very High Concern for Authorisation in accordance with Art. 59 (10) of the REACH Regulation (electronically accessible at: http://echa.europa.eu/candidate-list-table); or the intention, initiation or completion of a harmonised classifi cation as R 1A, H360 or as R 1B, H360;

(ii) in the context of the CAD the development of a recommendation by SCOEL;

(iii) at national level the derivation of an OEL in Germany or the Netherlands.

1.4 Method – specifi c selection criteria

In this section, the second step of the selection and diff erentiation process is addressed. By presenting detailed selection criteria, fi rst, the reduction of the


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number of actual regulatory reprotoxins is explained, and second, the grading of relevance is outlined.

1.4.1 Selection of actual regulatory reprotoxins

As indicated in the previous sub-section, two mechanisms were used for re-ducing the number of actual regulatory reprotoxins by more than 50 per cent in preparation for the subsequent examination of their registration status un-der REACH. Both are explained in detail below.

Omission of substances classifi ed as either carcinogens (C 1A, H350 or C 1B,

H350) or mutagens (M 1B, H340)

Reprotoxins that are also classifi ed as either carcinogens or mutagens are within the scope of the Carcinogens and Mutagens Directive (Dir. 2004/37/EC, hereafter: CMD). As a legal consequence, OELs for those substances can be derived only under the CMD and, thus, have to fulfi l the criteria of a bind-ing OEL (in short: BOEL) as specifi ed in Art. 16 paragraph 1 of the CMD. In other words, legally an OEL under the CAD cannot be derived for carcinogens or mutagens. Subsequently, such carcinogens or mutagens are omitted from the further analysis.

In contrast, reprotoxins that are at the same time potential regulatory car-cinogens are not omitted from the further analysis as the duration for their re-classifi cation as carcinogens (C 1A, H350 or C 1B, H350) is not predictable. Until then, they are within the scope of the CAD and an OEL might be war-ranted.

In the context of this report, a substance not classifi ed as a carcinogen (C 1A, H350 or C 1B, H350) is considered to be a ‘potential regulatory carcinogen’ if at least one of certain conditions, analogous to the ones employed for the defi nition of a ‘potential regulatory reprotoxin’ (cf. Section 1.3, sub-section ‘Reprotoxins’, above), is met: the existence of a notifi ed intention, initiation or fi nalisation of a process of harmonised classifi cation either as C 1A, H350 or as C 1B, H350; the existence of a classifi cation by the International Agency for Research on Cancer (IARC) either as ‘carcinogenic to humans’ (group 1) or as ‘probably carcinogenic to humans’ (group 2A); or the existence of a notifi ca-tion to the ECHA by one or more manufacturers or importers either as C 1A, H350 or as C 1B, H350, in conjunction with other supporting evidence, such as the inclusion in the risk management option analysis (RMOA), the inclu-sion in the Community Rolling Action Plan (CoRAP) or the derivation, or at-tempted derivation, of an exposure-risk-relationship at national level. Combination of reprotoxic compounds of certain elements to single entries

For most metals for which an OEL has been derived, the scope of the OEL usually covers both the metal itself and its compounds or, as the case may be, its inorganic compounds. In the case of reprotoxic substances, this

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pattern holds for lead and its inorganic compounds, and seems to be ap-plicable for two groups of boron compounds also, borates and perborates.

Table 1 provides an overview of the two groups of compounds classified as reprotoxins (inorganic lead compounds, boron compounds) combined into a single entry each, covering 39 entries in total in the C&L Inventory on the ECHA website.

Table 1 Reprotoxic compounds of certain elements combined into a single entry each

Reprotoxic compounds Number of individual entries in C&L Inventory on ECHA website

Inorganic lead compounds 16

Boron compounds: borates and perborates 23

1.4.2 Assessment of relevance of selected regulatory reprotoxins

The relevance of reprotoxins presumably placed on the market is graded ac-cording to either their registration status under REACH or their identifi cation as a substance used in medicinal products or approved for use in plant protec-tion products or biocidal products.

Relevance based on registration information

Less than 100 entries in the C&L Inventory on the ECHA website classifi ed as R 1A, H360 or as R 1B, H360 remained after the selection process described above. For each of them it was checked whether an entry existed in the data-base on registered substances on the ECHA website. Similarly, for each of the three combined entries for inorganic lead compounds, borates and perborates it was checked whether an entry existed in the registration database for at least one related compound.

In the same way, for all potential regulatory reprotoxins (identifi ed by search-ing the respective lists on the ECHA website addressed in Section 1.3, sub-section ‘Reprotoxins’, above) their registration status under REACH was checked.

According to the type of registration, four diff erent levels of relevance are defi ned for the purpose of this project:– ‘relevance’ for registration type ‘full’;– ‘limited relevance’ for registration type ‘intermediate’;– ‘unclear relevance’ for reprotoxins either registered as ‘NONS’ or without

registration which are, or have been, subjected to certain regulatory pro-cesses (as described in Section 1.3, sub-section ‘Relevant reprotoxins’);


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– ‘no relevance’ for reprotoxins without registration unless they meet the criterion described under ‘unclear relevance’, above.

This grading of the level of relevance of a reprotoxin registered under REACH is based on the underlying defi nitions and obligations stipulated in the REACH regulation for substances placed on the market. A precondition for placing reprotoxins on the market with a tonnage greater than one tonne per year is registration in accordance with Art. 6 of REACH. If the full spectrum of uses is to be covered, a complete registration is necessary in accordance with Art. 10 of REACH; if the reprotoxin is to be manufactured and used as an on-site isolated intermediate under strictly controlled conditions only, in accordance with Art. 17 of REACH a less detailed registration suffi ces. For re-protoxins manufactured and placed on the market below one tonne per year, registration is not requested.

The term ‘strictly controlled conditions’ entails that the substance be ‘rig-orously contained by technical means during the whole lifecycle’; workers should thus not be exposed to such substances during manufacture and use. Exposure might be possible, however, during control tasks and through re-pair and maintenance work. Due to these remaining possibilities for workers’ exposure, reprotoxins with registration as on-site isolated intermediates are still considered to be of limited relevance.

Due to the rather limited information publicly available for reprotoxins listed as NONS, their relevance status cannot be decided as, depending on their ac-tual use, they could have qualifi ed either for a full registration or for a regis-tration as on-site isolated intermediates had they been registered according to the REACH criteria for phase-in substances. Thus, they are considered to be of unclear relevance.

In contrast, reprotoxins placed on the market without any registration are generally considered to be of no relevance, although it is impossible to diff er-entiate whether they are manufactured and placed on the market not at all or below a tonnage of one tonne per year.

A subset of reprotoxins without any registration that are, or have been, sub-jected to one of the regulatory processes described in Section 1.3, sub-section ‘Relevant reprotoxins’, is considered to be of unclear relevance because the mere existence of such processes is indicative of a certain level of relevance. However, without additional information on the reasons for the respective process, that level cannot be specifi ed for the particular reprotoxin.

Relevance based on use category

Reprotoxins without any entry in the database on registered substances on the ECHA website, but listed either as an active substance approved for use in plant protection products or as a biocidal active substance are considered to be of limited relevance in the context of this report. This is due to two considerations:

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(i) in both regulations (on plant protection products and on biocidal prod-ucts) the approval of reprotoxins as active substances is supposed to be prohibited or restricted to stringent conditions;

(ii) in both regulations, an Acceptable Operator Exposure Level (AOEL) might be established as part of the approval process for an active substance; thus, the derivation of an OEL under the CAD would result in legal inter-ference and should not be considered to be a viable option, accordingly.

In contrast, reprotoxins without any entry in the database on registered sub-stances on the ECHA website, but used in medicinal products are considered to be of unclear relevance. This is due to the following aspects:– unavailability of any information on their actual use;– unavailability of any information on use conditions; – unavailability of any exposure information.

In addition, for this use category it remains to be discussed whether an OEL would be an appropriate regulatory tool or whether sector-specifi c control measures, analogous to those for laboratories, would be a better approach.

1.4.3 Refi nement of level of relevance of reprotoxins placed on the market

The information publicly available on substances with full registration al-lows further diff erentiation of the qualifi er ‘relevance’. This could be based in particular on two parameters: (i) the tonnage band for the production vol-ume; and (ii) the identifi ed uses, expressed as process categories primarily for manufacture, formulation, uses at industrial sites and uses by professional workers. Both pieces of information are available in the registration database on the ECHA website (http://echa.europa.eu/information-on-chemicals/registered-substances).

Due to the comparatively small number of substances identifi ed as ‘relevant reprotoxins’ (cf. Section 2.1), a further diff erentiation based on the tonnage band is considered to be of low added value and thus has not been done for the time being. Instead, for each reprotoxin with full registration the information on the tonnage band is listed in Tables 1–3 of the Annex.

In addition, we have tried to utilise the information on process categories (PROCs) as it facilitates deeper insight into potential exposure situations of workers. The following two process categories are considered to result in no exposure of workers, corresponding to the exposure situation of tasks involv-ing intermediates:(i) PROC 1: Use in closed process, no likelihood of exposure;(ii) PROC 3: Use in closed batch process (synthesis or formulation).

However, no substance was identifi ed for which solely PROC 1 or PROC 3 (or both) has been registered. Neither could any substance be identifi ed for which, in addition to PROC 1 or PROC 3, one or more of the following three


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PROCs have been registered: (a) PROC 15: Use as a laboratory agent;(b) PROC 0: Other: monomer in imported polymer;(c) PROC 0: Other: production of pharmaceuticals / vaccines.

As a result, the level of relevance was not reduced for any of the reprotoxins with full registration.

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2. Results

2.1 Substances toxic to reproduction selected with diff erent levels of relevance

Altogether 141 reprotoxins or groups of reprotoxins have been selected and are allocated to three diff erent relevance categories. These substances are listed in Tables 1–3 of the Annex.

2.1.1 Substances toxic to reproduction considered to be relevant

Based on the selection criteria described in Section 1.4 above, 66 reprotoxins are considered to be relevant and the derivation of an OEL is deemed ap-propriate for them; they are listed in Table 1 (Annex); 39 of them are actual regulatory reprotoxins, 27 are potential ones.

2.1.2 Substances toxic to reproduction considered to be potentially relevant

Based on the selection criteria described in Section 1.4 above, 28 reprotoxins are considered to be potentially relevant and are listed in Table 2 (Annex); 14 of them are actual regulatory reprotoxins, 14 are potential ones.

Nine of them are registered as intermediates only; the remaining 19 have no registration, but are included either in the database on biocidal active sub-stances or in the list of active substances authorised for use in plant protec-tion products.

2.1.3 Substances toxic to reproduction with unclear relevance

Based on the selection criteria described in Section 1.4 above, 47 reprotoxins are considered to be of ‘unclear relevance’ which are listed in Table 3 (Annex):– 18 of them are actual regulatory reprotoxins and four are potential ones

without registration under REACH and subject to one of the regulatory processes described in Section 1.3, sub-section ‘Relevant reprotoxins’;

– four of them are actual regulatory reprotoxins registered as NONS;


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– two of them are actual regulatory reprotoxins and 19 are potential ones without registration under REACH used in medicinal products and thus are exempted from the registration obligation under REACH.

2.2 Additional information in Tables 1–3 of the Annex

Additional information is provided in Tables 1–3 (Annex) in two diff erent ways, by subdividing each table in separate sections for specifi c classes of reprotoxins, and by entering notes in diff erent columns on individual sub-stances. This information might be useful for further refi nement of the level of relevance and for future decisions on the necessity of deriving an OEL for the respective reprotoxin.

2.2.1 Special classes of substances toxic to reproduction

In chapter 1, a number of special classes of substances are addressed. To en-able easier identifi cation of reprotoxins belonging to one of these classes, in Tables 1–3 (Annex) they are displayed as separate sub-sections: – substances notifi ed as new substances (NONS) under Dir. 67/548/EEC;– biocidal active substances or active substances authorised for use in plant

protection products PPP);– substances used in medicinal products.

2.2.2 Notes on classification, registration and regulatory processes

Tables 1–3 (Annex) comprise fi ve columns each:(i) name of substance or group of substances;(ii) CAS number, if available, otherwise EC number;(iii) classifi cation with regard to reproductive toxicity;(iv) registration status under REACH and tonnage band, if available;(v) additional comments.

Standard information in column (iii) is the harmonised classifi cation with regard to reproductive toxicity as available from Annex VI of the CLP regu-lation. For reprotoxins for which the intention of a process of harmonised classifi cation was notifi ed, or for which such a process was initiated, the intended or proposed harmonised classifi cation is specifi ed. For reprotox-ins without such information, the notifi ed self-classifi cation of the manufac-turer or importer is specifi ed. For potential regulatory carcinogens (that is, substances without a harmonised classifi cation as a carcinogen (C 1A / 1B)) which are classifi ed by IARC as Group 1 or Group 2A carcinogens, also the IARC classifi cation together with its year of publication is specifi ed.

Standard information in column (iv) for reprotoxins with a full registration is the tonnage band; for other reprotoxins it is specifi ed whether they are

Henning Wriedt

18 Report 137

registered as intermediates only, as NONS or not at all. Reprotoxins with both a full registration and one for use as intermediates are denoted by the additional note (a). Reprotoxins approved as active substances in plant pro-tection products are denoted by the entry ‘PPP’; and reprotoxins approved as biocidal active substances by the entry ‘biocidal active substance’. For reprotoxins used in medicinal products their use as anti-cancer drug is de-noted by the additional note (b).

For column (v) a variety of notes are foreseen, which are detailed in the Annex below Table 3 in sub-section ‘Explanation of notes in Tables 1–3’. Reprotoxins that are also potential regulatory carcinogens (cf. Section 1.4) are denoted by the additional note (c).

The numerical notes are ordered in four groups, referring to REACH and CLP processes; OSH processes and instruments at EU level; and OSH pro-cesses and instruments at Member State level. Information on OELs at Member State level is based on the GESTIS database on international limit values for chemical agents, available at: http://www.dguv.de/ifa/GESTIS/GESTIS-Internationale-Grenzwerte-f%C3%BCr-chemische-Substanzen-limit-values-for-chemical-agents/index.jsp or directly at: http://limitvalue.ifa.dguv.de/.

In particular, the numerical notes in column (v) are intended to facilitate access to additional publicly available information. For example, for the majority of REACH and CLP processes, substance-specifi c information – including information on use – is available at the ECHA website for the re-spective process.


Report 137 19

3. Discussion

Combining classifi cation information from the CLP regulation, on one hand, with registration information under REACH, information for plant protec-tion products, for biocidal products and for medicinal products, on the other, 141 reprotoxins or groups of reprotoxins have been identifi ed as relevant and allocated to three categories of diff erent level of relevance. Seventy seven of them are actual regulatory reprotoxins, 64 are potential ones. The category for the highest level of relevance comprises 66 reprotoxins (cf. Annex, Table 1) for which an OEL under the CAD might be suggested.

Of the remaining 75 reprotoxins, 19 are active substances authorised for use in biocidal or plant protection products. The specifi c legislation applicable to them should take precedence to OSH legislation so that for regulatory reasons the derivation of an OEL under the CAD does not seem to be a priority issue. Another 10 carcinogens are registered as intermediates only. Also for them the derivation of an OEL does not seem to be a priority issue.

Whether the derivation of an OEL under the CAD for any of the reprotoxins from the group of four NONS will become a priority issue will depend on the future availability of additional information, in particular on production or import volume, and on use patterns.

For the remaining 42 reprotoxins, 20 of which are used in medicinal prod-ucts, the currently available information, in particular on volume, use pat-terns and extent of exposure, is assessed as insuffi cient for suggesting the derivation of an OEL under the CAD. Should additional information become available, however, or the application of assessment criteria diff erent from the actual information be recommended, the derivation of an OEL for additional reprotoxins from this group might also be suggested.

Twenty of the 141 reprotoxins identifi ed as relevant are also potential regula-tory carcinogens (cf. Section 1.4), which means that they remain within the scope of the CAD until they are re-classifi ed as carcinogens (C 1A, H350 or C 1B, H350) and then would fall within the scope of the CMD. Nineteen of them are medicinal products and only one is a reprotoxin for which the derivation of an OEL is suggested.

For 12 of the 66 reprotoxins or groups of reprotoxins, for which the derivation of an OEL is suggested, an IOELV under the CAD is either already in existence

Henning Wriedt

20 Report 137

or is under preparation. For another 18 a health-based OEL in at least one EU Member State (MS) has been derived and might be used as a starting point for the derivation of an OEL under the CAD. Twenty-fi ve of the 30 reprotoxins with an OEL of either kind are actual regulatory reprotoxins, whereas just fi ve are potential ones.

For 59 of the 66 reprotoxins or groups of reprotoxins for which the derivation of an OEL is suggested, tonnage information is available from their registra-tion. In particular for 29 of the 36 reprotoxins without an IOELV or an OEL at MS level, that information might be used for further prioritisation of the deri-vation of an OEL under the CAD. For this purpose, the 14 substances in the three higher volume bands (1,000–1,000,000 t/a) might be given precedence over the 15 substances in the three lower volume bands (0–1,000 t/a).

For 15 of the 30 reprotoxins with either an IOELV under the CAD or an OEL at Member State level, information is available on whether the OEL is protec-tive not only for adverse fertility eff ects but also for developmental eff ects. For seven substances the OEL is supposed to be protective for both kinds of adverse eff ects, whereas for another eight, developmental eff ects cannot be excluded even when the respective OEL is achieved.


Report 137 21

AnnexTable 1 List of substances/groups of substances toxic to reproduction considered to be relevant

No. Substance/group of substances

CAS no. Harmonised (or notifi ed) classifi -cation

Registered tonnage band [t/a]

Comments

1 Benzyl butyl phthalate 85-68-7 R 1B, H360Df 1,000–10,000 3), 4: 2/2015;, 31)

2 1,2-Bis(2-methoxyethoxy) ethane

112-49-2 R 1B, H360Df 10–100 3)

3 Bis(2-(2-methoxyethoxy)ethyl) ether

143-24-8 proposed:R 1B, H360F

100+ 2: 12/2015

4 Bis(2-methoxyethyl) ether 111-96-6 R 1B, H360FD 100–1,000 H), 3), 4: 8/2017; 31), 35)

5 Boric acid and borates, boric oxide (diboron trioxide)

10043-35-3 1330-43-4 1332-77-0 1303-86-2

R 1B, H360FD 100,000–1,000,000, 1,000–10,000

3), 5), 9), 31), 34)

6 1-Bromopropane 106-94-5 R 1B, H360FD 1,000–10,000a)

H), 3), 5), 31)

7 4-tert-Butylbenzoic acid 98-73-7 R 1B, H360F 100–1,000a)

H), 7), 8), 31)

8 2-(4-tert-Butylbenzyl)propion-aldehyde

80-54-6 notifi ed:R 1B, H360

1,000–10,000 9), 10), 12)

9 n-Butyltin trichloride 1118-46-3 notifi ed:R 1B, H360

1,000+ 9)

10 Carbon monoxide 630-08-0 R 1A, H360D 1,000–10,000 23), 31), 35)

11 N-Carboxymethyl)iminobis (ethylenenitrilo)tetra(acetic acid) (DTPA acid)

67-43-6 to be proposed:R 1B, H360D

1,000 – 10,000 a)

8)

12 Dibutylbis(pentane-2,4-diona-to-O,O’)tin

22673-19-4 intended:R 1B, H360FD

100–1,000 1: 9/2015

13 Dibutyl phthalate 84-74-2 R 1B, H360Df 1,000–10,000a)

3), 4: 2/2015; 7), 26), 31), 34)

14 Dibutyltin dichloride 683-18-1 R 1B, H360FD 1,000–10,000 3), 36), 38)

15 Dibutyltin dilaurate 77-58-7 R 1B, H360FD 100–1,000 agreed at RAC-33

16 Dicyclohexyl phthalate 84-61-7 R 1B, H360D 100–1,000 to be included via 9. ATP7), 8), 31)

17 Di-(2-ethylhexyl) phthalate (DEHP)

117-81-7 R 1B, H360FD 100,000–1,000,000 a)

H), 3), 4: 2/2015; 31), 34)

18 Dihexyl phthalate 84-75-3 R 1B, H360FD not registered, but contaminant of

3), 6)

19 1,2-Benzenedicarboxylic acid, di-C6-10-alkyl esters

68515-51-5 100–1,000 3), 7), 8)

20 Diisobutyl phthalate 84-69-5 R 1B, H360Df 0–10a)

3), 4: 2/2015; 31)

21 Di-‘isononyl’ phthalate 28553-12-0 proposed: R 1B, H360Df

100,000–1,000,000 related to

2: 11/2015, 31)

22 1,2-Benzenedicarboxylic acid, di-C8-10-branched alkyl esters, C9-rich

68515-48-0 proposed: R 1B, H360Df

100,000–1,000,000 2: 11/2015

23 Diisopentyl phthalate 605-50-5 R 1B, 360FD 10–100 3), 5)

24 1,2-Dimethoxyethane 110-71-4 R 1B, 360FD 100–1,000 3), 31)

Table 1 List of substances/groups of substances toxic to reproduction considered to be relevant


CAS no. Harmonised (or notifi ed) classifi cation


Comments

25 N,N-Dimethylacetamide 127-19-5 R 1B, 360D 10,000–100,000 H), 3), 23), 31), 34)

26 N,N-Dimethylformamide 68-12-2 R 1B, 360D 10,000–100,000 a)

H), 3), 7), 8), 23), 31), 35)

27 Dinoseb (ISO) (2-tert-Butyl-4,6-dinitrophenol)

88-85-7 R 1B, 360Df 100–1,000 3)

28 Dioctyltin dilaurate 3648-18-8 intended: R 1B, H360D

100–1,000 1: 9/2015

29 2,3-Epoxypropyl methacrylate (glycidyl methacrylate)

106-91-2 proposed:R 1B, H360F

1,000–10,000 c) 2: 9/2014

30 Ethanol, 2,2’-iminobis-, N-(C13-15-odd numbered, branched and linear alkyl) derivs.

97925-95-6 intended: R 1B, H360FD

1,000–10,000 1: 6/2015

31 2-Ethoxyethanol 110-80-5 R 1B, H360FD 100–1,000 H), 3), 23), 31), 35)

32 Ethylene thiourea 96-45-7 R 1B, H360D 100–1,000 3), 31)

33 2-Ethylhexanoic acid 149-57-5 R2, H361 100,000–1,000,000 9), 10), 31)

34 2-Ethylhexyl 10-ethyl-4,4-dioctyl-7-oxo-8-oxa-3,5-dithia-4-stannatetradecanoate (Dioctyltin bis(2-ethylhexyl mercaptoacetate) (DOTE))

15571-58-1 intended: R 1B, H360FD

1,000–10,000 1: 2/20163), 7), 8), 36), 38)

35 3-Ethyl-2-methyl-2-(3-methylbutyl)-1,3-oxazolidine

143860-04-2 R 1B, H360F NONS, confi dential 3) mono constituent substance

36 N-Ethyl-2-pyrrolidone 2687-91-4 R 1B, H360D 1,000 + H), 36), 37)

37 Formamide 75-12-7 R 1B, H360D 10–100 a)

H), 3), 31)

38 Imidazole 288-32-4 R 1B, H360D 100–1,000 a)

7. ATP 9), 10)

39 4,4-Isobutylethylidenediphenol 6807-17-6 R 1B, H360F NONS, confi dential 7) polymer

40 4,4’-Isopropylidenediphenol (Bisphenol A)

80-05-7 R 1B, H360F 1,000,000–10,000,000

agreed at RAC-28 7), 9), 10), 23), 31), 34)

41 Lead (metallic) 7439-92-1 R 1A, H360DF 1,000,000–10,000,000

agreed at RAC-27 24), 26), 31)

42 Lead compounds, inorganic; e.g. tetralead trioxide sulphatelead monoxidetrilead dioxide phosphonate orange leadpentalead tetraoxide sulphate lead dioxide

12202-17-4 1317-36-8 12141-20-7 1314-41-6 12065-90-6 1309-60-0

R 1A, H 360Df IARC: 2A (2006)

1,000,000–10,000,000

b)3), 4: 5/2015; 6), 7), 8), 24), 26), 31)

Lead alkyl compounds R 1A, H360Df H)

43 Tetraethyl lead 78-00-2 notifi ed: R 1A, H360

1,000–10,000 H), 3), 31), 35)

44 Mercury 7439-97-6 R 1B, H360D 100–1,000 H), 7), 8), 23), 31)

45 2-Methoxyethanol 109-86-4 R 1B, H360FD 1,000–10,000 H), 3), 23), 31), 35)

46 2-Methoxyethyl acrylate 3121-61-7 notifi ed: R 1B, H360

100– 1,000 1: 12/2015, 11)

47 N-Methylacetamide 79-16-3 R 1B, H360D confi dential 3)

48 2-Methylimidazole 693-98-1 proposed: R 1B, H360D

confi dential a)

2: 2/2016

22 Report 137

Henning Wriedt


Report 137 23

Table 1 List of substances/groups of substances toxic to reproduction considered to be relevant


CAS no. Harmonised (or notifi ed) classifi cation


Comments

49 2-Methyl-1-(4-methylthiophenyl)-2-morpholinopropan-1-one

71868-10-5 R 1B, H360FD 1,000–10,000 agreed at RAC-33

50 N-Methyl-2-pyrrolidone 872-50-4 R 1B, H360D 10,000–100,000 H), 3), 23), 31), 34)

51 Mixture of two components: N-(1,3-dimettylbutyl)-N’-phenyl-p-phenylenediamine N1-(1,3-dimethylbutyl)-N4-(4-(1-methyl-1-phenylethyl)-phenyl)benzene-1,4-diamine

EC number: 448-020-2

notifi ed:R 1B, H360

100–1,000 9)

52 Nitrobenzene 98-95-3 R 1B, H360F 100,000–1,000,000 a)

H), 3), 7), 8), 23), 31)

53 Pentasodium (carboxylato-methyl)iminobis(ethylenenitrilo) tetraacetateNa5DTPA

140-01-2 to be proposed: R 1B, H360

10,000–100,000 a)

7), 8)

54 Perboric acid, sodium salt 11138-47-9 7632-04-4

R 1B, H360Df 10,000–100,000 3), 6)

55 Phenol, dodecyl-, sulfurized, calcium salts

68855-45-8 notifi ed: R 1B, H360

1,000–10,000 9), 12)

56 Potassium permanganate 7722-64-7 proposed: R 1B, H360Df

1,000–10,000 2: 2/2015

57 Retinol 68-26-8 notifi ed: R 1B, H360

0–10 7), 8), 11)

58 Retinyl propionate 7069-42-3 notifi ed: R 1B, H360

0–10 7), 8), 11)

59 Tetrahydrofurfuryl alcohol 97-99-4 R 1B, H360Df 1,000–10,000

60 Tetrahydrothiopyran-3-carbox-aldehyde

61571-06-0 R 1B, H360D confi dential

61 Tetrapropenylphenol (TPP), (Phenol, dodecyl-, branched)

121158-58-5 R 1B, H360F 10,000–100,000 a)

agreed at RAC-27

62 Theophylline 58-55-9 intended: R 1B, H360D

0–10 a)

1: 9/2015; 31)

63 Tris(2-chloroethyl)phosphate 115-96-8 R 1B, H360F 10–100 3), 4: 8/2015

64 Tris(2-methoxyethoxy)vinyl-silane

1067-53-4 notifi ed: R 1B, H360Df

1,000–10,000 7), 12)

65 Trixylyl phosphate 25155-23-1 R 1B, H360F 100–1,000 3), 6), 7)

66 1-Vinylimidazole 1072-63-5 proposed: R 1B, H360D

confi dential 2: 6/2015

Henning Wriedt

24 Report 137

Table 2 List of additional substances/groups of substances toxic to reproduction considered to be potentially relevant

Substance/group of substances

CAS no. Harmonised classifi cation


Comments

2-(2-Aminoethylamino)ethanol

111-41-1 R 1B, H360Df intermediate only 31)

2-Bromopropane 75-26-3 R 1A, H360F intermediate only 31)

2-Butyryl-3-hydroxy-5-thiocyclohexan-3-yl-cyclohex-2-en-1-one

94723-86-1 R 1B, H360D intermediate only

Chloromethylene dimethyl-ammonium chloride

3724-43-4 R 1B, H360D intermediate only

Cyclic 3-(1,2-Ethanediylacetale)-estra-5(10),9(11)-diene-3,17-dione

5571-36-8 R 1B, H360F intermediate only

Methoxyacetic acid 625-45-6 R 1B, H360FD intermediate only H), 3); 31), 35)

N-Methylformamide 123-39-7 R 1B, H360D intermediate only

Quinolin-8-ol (8-hydroxyquinoline)

148-24-3 R 1B, H360D intermediate only agreed at RAC-33

Tributyltin compounds (Bis(tributyltin) oxide; Tributyltin chloride)

(56-35-9 1461-22-9)

R 1B, H360FD intermediate only agreed at RAC-27 3), 25), 31), 34)

Biocidal active substances or active substances authorised for use in plant protection products (PPP)

Brodifacoum (ISO) 56073-10-0 R 1A, H360D biocidal active substance

agreed at RAC-28

Bromadiolone (ISO) 28772-56-7 R 1B, H360D biocidal active substance; PPP

agreed at RAC-28

Carbetamide (ISO) 16118-49-3 R 1B, H360D PPP agreed at RAC-32

Chlorophacinone (ISO) 3691-35-8 R 1B, H360D biocidal active substance

agreed at RAC-28

Coumatetralyl (ISO) 5836-29-3 R 1B, H360D biocidal active substance

agreed at RAC-28

Cyproconazole (ISO) 94361-06-5 R 1B, H360D biocidal active substance

agreed at RAC-34

Difenacoum (ISO) 56073-07-5 R 1B, H360D biocidal active substance; PPP

agreed at RAC-28

Difethialone (ISO) 104653-34-1 R 1B, H360D biocidal active substance

agreed at RAC-28

Epoxiconazole (ISO) 135319-73-2 133855-98-8 106325-08-0

R 1B, H360Df PPP

Flocoumafen (ISO) 90035-08-8 R 1B, H360D biocidal active substance

agreed at RAC-28

Flumioxazin (ISO) 103361-09-7 R 1B, H360D PPP 2: 6/2015: R 2, H361d

Flusilazole (ISO) 85509-19-9 R 1B, H360D PPP

Glufosinate (ISO) 77182-82-2 R 1B, H360Fd PPP

Linuron (ISO) 330-55-2 R 1B, H360Df PPP

Quizalofop-P-tefuryl 119738-06-6 200509-41-7

R 1B, H360Df PPP 2: 9/2014: R 2, H361fd

Thiacloprid (ISO) 111988-49-9 R 1B, H360FD biocidal active substance; PPP

agreed at RAC-32

Triadimenol (ISO) 55219-65-3 R 1B, H360 PPP agreed at RAC-34


Report 137 25

Table 2 List of additional substances/groups of substances toxic to reproduction considered to be potentially relevant (cont.)




Comments

Trifl umizole (ISO) 68694-11-1 99387-89-0

R 1B, H360D PPP agreed at RAC-31

Warfarin (ISO) 81-81-2 R 1A, H360D biocidal active substance; PPP a)

H), 31), 35)

Table 3 List of additional substances/groups of substances toxic to reproduction considered to be of unclear relevance




Comments

Ammonium pentadecafl uoro-octanoate (APFO)

3825-26-1 R 1B, H360D not registered 3), 31)

1,2-Benzenedicarboxylic acid, di-C6-8-branched alkyl esters, C7-rich

71888-89-6 R 1B, H360D not registered 3), 5)

1,2-Benzenedicarboxylic acid, di-C7-11-branched and linear alkyl esters

68515-42-4 R 1B, H360Df not registered 3), 5)

1,2-Benzenedicarboxylic acid, dipentyl ester, branched and linear

84777-06-0 R 1B, H360FD not registered 3), 5)

Bis(2-methoxyethyl) phthalate 117-82-8 R 1B, H360Df not registered 3), 5)

1,2-Diethoxyethane 629-14-1 R 1A, H360Df not registered 3)

Dihexyl phthalate 84-75-3 R 1B, H360FD not registered cf. no. 18 in table 1

Diisohexyl phthalate 71850-09-4 proposed: R 1B, H360FD

not registered 2: 12/2015

Diisohexyl phthalate (DIHP) (1,2-Benzenedicarboxylic acid, dihexyl ester, branched and linear)

68515-50-4 R 1B, H360FD not registered 7. ATP 3), 6)

Diisooctyl phthalate 27554-26-3 intended: R 1B

not registered 1: 2/2016

Di-n-pentyl phthalate 131-18-0 R 1B, H360FD not registered 3), 5)

Diphenylether; octabromo derivate

32536-52-0 R 1B, H360Df not registered 25)

2-Ethoxyethyl acetate 111-15-9 R 1B, H360FD not registered H), 3), 23), 31), 35)

2-Methoxyethyl acetate 110-49-6 R 1B, H360FD not registered H), 23), 31), 35)

2-Methoxypropanol 1589-47-5 R 1B, H360D not registered H), 31), 35)

2-Methoxypropyl acetate 70657-70-4 R 1B, H360D not registered H), 31), 35)

Nickel tetracarbonyl 13463-39-3 R 1A, H360D not registered 31)

Nonadecafl uorodecanoic acid; ammonium nonadecafl uoro-decanoate; sodium nona-decafl uorodecanoate

335-76-2 3108-42-7 3830-45-3

R 1B, H360Df not registered agreed at RAC-35 7)

N-Pentyl-isopentylphthalate 776297-69-9 R 1B, H360FD not registered 3), 5)

Henning Wriedt

26 Report 137

Table 3 List of additional substances/groups of substances toxic to reproduction considered to be of unclear relevance (cont.)




Comments

Perfl uorononan-1-oic acid and its sodium and ammo-nium salts

375-95-1 21049-39-8 4149-60-4

R 1B, H360Df not registered agreed at RAC-30 3), 7), 8)

Perfl uorooctanoic acid (PFOA) and its salts

335-67-1 3825-26-1

R 1B, H360D not registered H), 3), 36), 38)

Perfl uorooctane sulfonic acid and its salts

1763-23-1 2795-39-3 29081-56-9 29457-72-5 70225-14-8

R 1B, H360D not registered H), 31), 35)

Tetramethyl lead 75-74-1 notifi ed: R 1A, H360

not registered H), 31), 35)

Substances notifi ed as new substances (NONS) under Dir. 67/548/EEC

(E)-3-[1-[4-[2-(Dimethylamino) ethoxy]phenyl]-2-phenylbut-1-enyl]phenol

82413-20-5 R 1B, H360F NONS, confi dential polymer

N,N-(Dimethylamino) thio-acetamide hydrochloride

27366-72-9 R 1B, H360D NONS, confi dential polymer

(4-Ethoxyphenyl)(3-(4-fl uoro-3-phenoxyphenyl)propyl) dimethylsilane

105024-66-6 R 1B, H360F NONS, confi dential polymer

2-[2-Hydroxy-3-(2-chlorophenyl) carbamoyl-1-naphthylazo]-7-[2-hydroxy-3-(3-methylphenyl) carbamoyl-1-naphthylazo] fl uoren-9-one

151798-26-4 R 1B, H360D NONS, confi dential polymer

Substances used in medicinal products

5-Azacytidine 320-67-2 notifi ed: R 1B, H360 IARC: 2A (1990)

not registeredb)

c)12)

Azathioprine 446-86-6 notifi ed:R 1A / 1B, H360IARC: 1 (2012)

not registered c)11), 41)

1,3-Bis(2-chloroethyl)-1-nitrosourea (BCNU) (Carmustine)

154-93-8 notifi ed:R 1B, H360IARC: 2A (1987)

not registeredb)

c)

Busulfan (1,4-Butanediol-bis(methanesulfonate))

55-98-1 notifi ed:R 1A, H360IARC: 1 (2012)

not registeredb)

c)12)

Bleomycin (sulphate) 9041-93-4 notifi ed:R 1B, H360 IARC: 2B (1987)

not registeredb)

c)12), 42)

Chlorambucil 305-03-3 notifi ed:R 1A / 1B, H360IARC: 1 (2012)

not registeredb)

c)12)

Chloramphenicol 56-75-7 notifi ed:R 1B, H360IARC: 2A (1990)

not registered c)12), 31)

1-(2-Chloroethyl)-3-cyclo-hexyl-1-nitrosourea (CCNU) (Lomustine)

13010-47-4 notifi ed:R 1B, H360 IARC: 2A (1987)

not registeredb)

c)12)


Report 137 27

Table 3 List of additional substances/groups of substances toxic to reproduction considered to be of unclear relevance (cont.)




Comments

1-(2-Chloroethyl)-3-(4-methylcyclohexyl)-1-nitrosourea (Methyl-CCNU) (Semustine)

13909-09-6 notifi ed:R 1B, H360 IARC: 1 (2012)

not registeredb)

c)

Cisplatin 15663-27-1 notifi ed:R 1B, H360IARC: 2A (1987)

not registeredb)

c)12), 41)

Cycloheximide 66-81-9 R 1B, H360D not registered

Cyclophosphamide 50-18-0 6055-19-2

notifi ed:R 1A / 1B, H360IARC: 1 (2012)

not registeredb)

c)11)

Cyclosporin 59865-13-3 79217-60-0

notifi ed:R 1A / 1B, H360IARC: 1 (2012)

not registered c)11)

Etoposide 33419-42-0 notifi ed:R 1A / 1B, H360IARC: 1 (2012)

not registeredb)

c)12)

Ketoconazole 65277-42-1 R 1B, H360F not registered

Melphalan 148-82-3 notifi ed:R 1A, H360IARC: 1 (2012)

not registeredb)

c)12)

Mitomycin C 50-07-7 notifi ed:R 1A / 1B, H360 IARC: 2B (1987)

not registeredb)

c)12), 42)

Procarbazine hydrochloride 366-70-1 notifi ed:R 1A / 1B, H360IARC: 2A (1987)

not registeredb)

c)41)

Tamoxifen 10540-29-1 notifi ed:R 1A / 1B, H360IARC: 1 (2012)

registered as inter-mediate onlyb)

c)7)

Teniposide 29767-20-2 notifi ed:R 1B, H360IARC: 2A (2000)

not registeredb)

c)12)

Thiotepa (Tris(1-aziridinyl)phosphine sulfi de)

52-24-4 notifi ed:R 1B, H360 IARC: 1 (2012)

not registeredb)

c)12), 42)

Henning Wriedt

28 Report 137

Explanation of notes in Tables 1–3

Column ‘Harmonised classifi cation’:

IARC: IARC classifi cation; year of publication.

Column ‘Registered tonnage band’:

a) additional registration(s) for ‘intermediate use only’.b) use as anti-cancer drug.

Column ‘Comments’:

c) substance is also a potential regulatory carcinogen.

re. REACH and CLP processes

1) Intention of CLH process notifi ed; date of notifi cation.2) CLH process initiated; date of initiation.3) Substance (or compounds of it) included in REACH candidate list (accord-

ing to Art. 59 (10)).4) Substance (or compounds of it) included in REACH authorisation list; sun-

set date.5) Inclusion of substance (or compounds of it) in REACH authorisation list

recommended by ECHA.6) Inclusion of substance (or compounds of it) in REACH authorisation list

considered by ECHA (consultation phase).7) Substance (or compounds of it) included in risk management option analy-

sis (RMOA).8) RMOA result available.9) Substance (or compounds of it) included in Community Rolling Action

Plan (CoRAP).10) Substance evaluation report (or other substance evaluation documents)

available.11) Notifi ed classifi cation submitted by majority of notifi ers.12) Notifi ed classifi cation submitted by some notifi ers only.

re. OSH processes and instruments (at EU level)

23) IOELV under the CAD in existence or in preparation.24) BOEL under the CAD in existence.25) SCOEL recommendation published.26) SCOEL recommendation under development.

re. OSH processes and instruments (at MS level)

31) Health-based OEL derived in at least one EU Member State.34) Additional notation in Germany: the health-based OEL is protective also

for developmental eff ects.35) Additional notation in Germany: developmental eff ects cannot be excluded

even when the health-based OEL is achieved.36) Health-based MAC value derived by German MAC Commission.37) The health-based MAC value is, in addition, protective for developmental

eff ects.


Report 137 29

38) Developmental eff ects cannot be excluded even when the health-based MAC value is achieved.

41) Exposure–risk relationship (ERR) derived (in the Netherlands).42) ERR not derivable (in the Netherlands).

Documents

Reprotoxins that should be subject to limit values for ...€¦ · area of reprotoxic substances in the scope of their national legislation con-cerning carcinogenic and mutagenic